Narcotic medicaments



Patented Mar. 3, 1953 UNITED STATES PATENT OFFICE No Drawing.Application September 25, 1948, Serial No. 51,299

lClaim. 1

This invention relates to new pharmaceutical products and has particularrelation to new and improved narcotics consisting of mixtures of severalactive ingredients.

It is known that in the application to patients of various compoundshaving a narcotic effect, such as morphine, codeine, their salts andrerivatives, and other products having morphinelike physiologicaleffects, certain unwelcome phenomena, for example nausea, vomiting andreduction of biliary and pancreatic secretions often occur. It also wasobserved that when certain other drugs were administered simul taneouslywith the narcotics, for instance drugs having parasympathetic depressantproperties, some side effects made themselves less felt. However, noneof these drugs reduce the incidence of side-actions greatly and many ofthem do not relax spasms induced by most of the opium-derivatives.

It has now been found that improved narcotic preparations are obtainedif narcotic compounds, such as opium derivatives and other compoundswith morphine-like action, are used in mixture with those syntheticantispasmodic drugs which exert powerful musculotropic and neurotropiceffects and give relief of unstriated muscle spasms in gastrointestinal,biliary and genitourinary tract disorders. The addition of one or moreof these anti-spasmodic drugs to narcotics produces beneficial results,consisting in diminished untoward effects and in making the nature ofthese effects milder, when they occur. Unexpectedly it was found thatwhen narcotics are administered in combination with the antispasmodicsaccording to my invention, the analgesic action usually will startfaster than when the narcotic is given by itself. Furthermore, theanalgesic action frequently is more potent and often lasts longer thanwhen no such anti-spasodic is given. It has also been found that thetoxicity of the preparations embodying the present invention is lowerthan the toxicity of the individual ingredients so that larger doses canbe administered safely.

In order to fully disclose my invention, I will now describe a number ofexamples illustrating some preferred embodiments of the invention.

Example 1.- parts of morphine sulphate by weight are mixed with 1.5parts of homatropine methylbromide by weight. This mixture interferesless with the propulsive movement of the small bowel than morphine aloneand increases the muscular tone less. It can, therefore, be used withbenefit before and after operations 2 and causes the patient lessdistress than morphine administered by itself. It does not produce someof the unpleasant side-eifects ofmorphine combined with atropine andgives the patient faster relief. Dose: 2.5-10 mgm.

Ewample 2.-Four parts of dihydrocodeinone terephtalate by weight aremixed with ten parts of diphenylacetyldiethylaminoethanol hydrochlorideby weight. This mixture can be given on an empty stomach withoutnauseating the patient, in contrast to dihydrocodeinone by itself whichshould be administered immediately following meals. It can, therefore,be used in cases where patients do not eat well or where patientsalready are subjected to emetic influences as for instance in whoopingcough. Relief from cough is longer than from dihydrocodeinone alone;Dose: 7-21 mgm.

Example 3.--50 parts of ethyl l-methyl-lphenylpiperidinel-carboxylatehydrochloride by weight are mixed with parts of beta-diethylamino-ethylfluorene-Q-carboxylate hydrochloride by weight. This mixture can begiven in larger doses than the analgesic alone, but will cause lessgastrointestinal irritability, less gastric hypermotility, less flushingand less sweating. Dose: 100-250 mgm.

Example 4.-Two parts of dihydromorphinone hydrochloride by weight aremixed with fifty parts of the phosphate of the d,l-tropic acid ester of3-diethylamino-2,2-dimethyl-l-propanol by weight. This mixture tends torelax the intestinal musculatureso that it will still further reduce theconstipating effects of dihydromorphinone, which are less than those ofmorphine. As dihydromorphinone is widely used in cancer and otherchronic diseases where patients often are bedridden and already tend toconstipate and where the analgesic drug has to be administered overprolonged periods of time, it is important to obtain the weakestconstipational eifects possible. Dose: 40-100 mgm.

Example 5.Five parts of dihydrohydroxycodeinone hydrochloride by weightare mixed with fifty parts of methylamino-iso-octene mucate by weightand one part of homatropine methylbromide by weight. The peristalticwaves in the colon, which may disappear upon administration ofdihydrohydroxycodeinone hydrochloride are less influenced by thismixture and the tone of the musculature of the large bowel is seldomincreased to the point of spasm. Feces are therefore less desiccated andthe tone of the anal sphincter less augmented. Dose: 2*5-75 mgm.

Example 6.-30 parts of codeine phosphate by Weight are mixed with 60parts of bis-gammaphenylpropylethylamine citrate by weight. Restlessnessand excitement are seldom seen from this mixture even when given inlarge doses. Miosis, nausea and constipation are less prominent thanfrom the same quantity of codeine administered without antispasmodic.Dose 50- 100 mgm.

The preparations according to my invention may be used in the form oftablets, capsules, solutions, and suppositories and they may beadministered by injection, per os or into the rectum.

In preparing the tablets, solutions and the like, accompanyingingredients, such as binders, diluents, lubricating agents, stabilizersand the like may be used. For example, tablets of the compositionaccording to Example 1 may be prepared from the following ingredients:

Morphine sulphate "grams" 250 Homatropine methylbromide do 37 Milk sugar5-2-725 Dextrine white 0-541 Starch 1-6- 220 Talc 0-6- 109 Zinc stearate0-2- 220 Water, Sumcient quantity.

From the above ingredients 25,000 tablets each containing ten mgm.morphine sulphate and one and one hall mgm. homatropine methylbromidemay be obtained by tabletting, each tablet to weigh 2.25 grains. Themixtures described in the other examples may be converted into tabletsin a substantially similar manner.

In order to prepare an iniectable solution of the product according toExample 2, one hundred and forty grams of the mixture are dissolved inten thousand ccm. of an isotonic solution and one thousand multiple doserubber stoppered ten cc. vials are filled.

My invention is not restricted to the specific ingredients andproportions and other details described in the above examples, and othernarcotics and other synthetic antispasmodics, combining musculotropicwith neurotropic effects, may be used to form mixtures embodying myinvention. The narcotics and antispasmodics may be used in forms otherthan those described above, for example in the form of their salts withother suitable organic or inorganic acids, in the form of the free baseor in the form 01' derivatives showing the desired narcotic andantispasmodic effect, respectively, and two or more narcotics and/or twoor more antispasmodics in any form to each mixture.

As further examples of synthetic antispasmodics adapted to be used incarrying out my invention, the following may be mentioned: betadiethylaminoethyl phenylpropylacetate, beta diethylaminoethylphenylcyclohexylacetate hydrochloride, beta diethylaminoethylphenylbenzylacetate.

The term synthetic antispasmodic is used in the present specificationand claims to denote any antispasmodic compounds which combinemusculotropic with neurotropic effect, do not 'codeine,dihydrocodeinone, l-methyli-phenylpiperidine-4-carboxylate,6-dimethylamino-4,4- diphenyl-B-heptanone, dihydromorphinone,dihydro-hydroxycodeinone, and salts and narcotic derivatives of thesecompounds, and other compounds or products having similar physiologicaleffects.

While my invention has been described in connection with certainpreferred embodiments of the same, it is not limited to the specificdetails disclosed and may be carried out wih various additions,substitutions and modifications, without departing from the spirit ofthe invention as defined in the appended claim.

The term unit dose is used to denote a single dose of the compositionclaimed, administered to an adult for therapeutic purposes.

What I claim is:

A new narcotic composition, in which the active ingredients consist of amajor amount of narcotic compounds and a minor amount of anantispasmodic, and in which the narcotic ingredients consist, per unitdose, or at least one compound selected from the group consisting of atleast 11.7 mg. codeine, at least 1.56 mg. dihydrocodeinone, at least1.35 mg. dihydromorphinone and at least 1.97 mg. dihydrohydroxycodeinonecompounds, and their salts, and the antispasmodic is homatropinemethylbromide.

MOZES JUDA LEWENSTEIN.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Name Date Diehl Jan. 14, 1926 OTHER REFERENCESNumber

